SUMMARY Intestinal inflammation is the basis of colitis and the human inflammatory bowel diseases (IBDs) that include Crohn?s disease and Ulcerative Colitis (UC). These inflammatory syndromes arise primarily from unknown environmental triggers deduced from studies of various human populations. Pathogen infection has been considered as a possible trigger, and seasonal infections have been associated with increased IBD diagnoses. We considered that recurrent low?grade infections such as occur in mild cases of human food poisoning may represent an environmental trigger. We therefore developed a mouse model of human food poisoning using low? titer non?lethal gastric infections of Salmonella enterica Typhimurium (ST). The Gram-negative ST bacterium is widespread and remains a leading cause of human foodborne disease. We have found that recurrent infections arising long after the host has cleared the previous infection caused a chronic inflammation and progressive colitis. We have determined that disease onset pathogen disruption of a protective mechanism in the host involving regulation of the anti-inflammatory enzyme Intestinal Alkaline Phosphatase (IAP) produced by enterocytes. ST infection resulted in Toll-like-receptor-4 (Tlr4)-dependent induction of neuraminidase (Neu) activity resulting in IAP desialylation and internalization, thus accelerating a mechanism of protein aging and turnover. The resulting IAP deficiency reduces the dephosphorylation and detoxification of pro-inflammatory lipopolysaccharide-phosphate species produced by commensal bacteria of the colon thereby causing a persistent Tlr-4-dependent inflammation leading to colitis. Similar alterations of IAP and Neu activity are reported in recent studies of human IBD patients. However, multiple simultaneous pathogenic mechanisms are believed to exist and are necessary to explain for example the thinning and erosion of the protective mucin barrier of the colonic epithelium, which normally provides a physical barrier to microbes and their inflammatory signals. This barrier erodes by unknown mechanisms with increased age and more rapidly in the onset of colitis resulting in bacterial contact with host epithelial cells that can cause inflammation and susceptibility to infection. We have recently discovered increased Neu activity in the colon of mice undergoing recurrent nonlethal gastric ST infections, with a coincident desialylation of Mucin-2 (Muc2), the major component of the adherent protective colonic mucin barrier lining the luminal epithelial surface. This is associated with thinning and erosion of the adherent mucin barrier, with reductions of Muc2 protein in the absence of changes in Muc2 RNA expression. Our data suggest a novel hypothesis involving the mechanism of age-related and pathogenic erosion of the epithelial mucin barrier due to Muc2 desialylation, possibly involving host Neu3, and leading to the increased proteolysis of multimeric Muc2 networks that compose this barrier. Research proposed herein will determine whether Muc2 desialylation directly leads to the erosion of the protective mucin barrier and will relatedly determine whether the preservation of this barrier prevents the onset of inflammation and colitis.